Browsing Pathways

Galactosemia (GALT Deficiency; GALT; Galactose-1-Phosphate Uridylyltransferase Deficiency) is a rare genetic disorder caused by a mutation in the GALT gene which codes for galactose-1-phosphate uridylyltransferase. A deficiency in this enzyme results in accumulation of D-galactose and galactitol in plasma and urine; bilirubin, chloride, and galactose-1-phosphate, and transaminases in serum. Symptoms, which present at birth, include jaundice, enlarged liver, anemia, weight loss, and vomiting. Treatment includes galactose-free diet, antibiotics, and vitamin K.

Gamma-Glutamyltransferase Deficiency is an autosomal recessive disorder caused by a mutation in the GGT1 gene which codes for gamma-glutamyltranspeptidase 1. A deficiency in this enzyme results in accumulation of L-cysteine, gamma-glutamylcysteine, and glutathione in urine. Symptoms, which present at birth, include tall stature, psychosis, and mental retardation.

Gaucher disease, also known as glucocerebrosidase deficiency, acid beta-glucosidase deficiency or GBA deficiency, refers to a group of autosomal recessively inherited rare inborn error of metabolism (IEM) that affect the sphingolipid metabolism pathway. All forms of Gaucher disease is caused by a mutation in the GBA gene that encodes lysosomal acid glucosylceramidase, an enzyme that is responsible for catalyzing the formation of ceramide and glucose from glucosylceramide via a hydrolysis reaction. Gaucher disease is characterized by the intracellular buildup of glucosylceramides, particularly in phagocytes, forming what are known as Gaucher cells. Symptoms include anemia, fatigue, hepatomegaly and splenomegaly, however these may vary based on the type of Gaucher disease. For example, type 1 (GD1) involves hepato- and splenomegaly, and types 2 and 3 (GD2 and GD3) also typically affect the brain and spinal cord, and as such tend to be more severe and more likely to become lethal. Treatment for Gaucher disease includes enzyme replacement therapy for type 1, which also helps treat types 2 and 3, but as the enzymes cannot cross the blood-brain barrier, cannot help with the brain damage associated with these types. A drug called miglustat, sold as Zavesca, can also be used to treat the symptoms of type 1 Gaucher disease in individuals who cannot have enzyme replacement therapy. It is estimated that Gaucher disease affects 1 in 100,000 individuals, with the rates being higher in certain populations such as Ashkenazi Jews. GD1 is the most common in most populations representing around 90% of cases of Gaucher disease, with GD2 and GD3 representing roughly 5% each.

Globoid Cell Leukodistrophy (GLD), also called Krabbe disease and galactosylceramide lipidosis, is an extremely rare inherited inborn error of metabolism (IEM). It is a degenerative disorder that affects the nervous system. It has an estimated prevalence of 1/100,000 in the Northern European population and a worldwide incidence of 1/100,000-1/250,000 live births. GLD is an autosomal recessive disorder that is caused by a deficiency of an enzyme called galactosylceramidase. Galactosylceramidase is a lysosomal protein that hydrolyzes the galactose ester bonds of ceramides and ceramide derivatives including galactocerebroside, galactosylsphingosine (psychosine), lactosylceramide, and monogalactosyldiglyceride. More specifically, galactosylceramidase is an enzyme that is involved in the catabolism (via the removal of galactose) of galactosylceramide, a major lipid in myelin, kidney, and epithelial cells of the small intestine and colon. Defects in galactosylceramidase lead to the accumulation of cytotoxic psychosine, which ultimately leads to apoptosis of oligodendrocytes and demyelination. As a result, this enzyme deficiency impairs the growth and maintenance of myelin, the protective sheath around nerve cell axons that ensures that electrical impulses are rapidly transmitted. GLD is part of a group of disorders known as leukodystrophies, which result from the loss of myelin (demyelination). GLD is also characterized by the abnormal presence of globoid cells, which are globe-shaped cells that often have multiple nuclei. There are three different phenotypes for GLD: infantile, juvenile, and late-onset. Neurodegeneration and early death (at age 2-3) occur in most infantile cases. In juvenile patients, the disease is often fatal 2-7 years after the symptoms begin. Adult-onset patients can survive many years after symptoms first manifest. The symptoms of infantile GLD usually begin during the first year of life. Typically, the initial signs and symptoms include feeding difficulties, episodes of fever without any sign of infection, irritability, stiff posture, muscle weakness, and slowed mental and physical development. Muscles continue to weaken as the disease progresses which decreases the infant's ability to move, chew, swallow, and breathe. It is also common for affected infants to experience vision loss and seizures. Treatment is limited to hematopoietic stem cell transplantation in pre-symptomatic infantile patients and mildly affected late-onset patients. Stem cell transplants have been shown to slow the progression of the disease.

SGLT2 is a sodium/glucose co-transporter that exists almost exclusively in kidney tissue. It is responsible for approximately 90% of the kidney's reabsorption of glucose, and can be found in the S1 segment of the proximal convoluted tubule of the nephron. A defect in the SLC5A2 gene that codes for SGLT2 results in glucosuria, due to the inability of most of the glucose to be reabsorbed by the kidney. There are some drugs that inhibit SGLT2 and are used to decrease blood sugar in patients with type 2 diabetes mellitus.

Glutaric Aciduria Type 1 is a rare autosomal recessive disease caused by a mutation in the GCDH which codes for glutaryl-CoA dehydrogenase. A deficiency in this enzyme results in accumulation of 3-hydroxybutyric acid, 3-hydroxyglutaric acid, glutaconic acid, glutaric acid, and ketone bodies in urine. Symptoms include encephalopathy, grimacing, dystonia, metabolic acidosis, and hygroma. Treatment includes a low-protein diet, L-carnitine, riboflavin, and anticonvulsants.

Glutathione Synthetase Deficiency (5-Oxoprolinuria; Pyroglutamic Aciduria; GSD) is a rare inborn error of metabolism (IEM) which arises from a disfunctional gene called GSS. This gene is responsible for glutathione synthetase. Glutathione synthetase is the second enzyme in the glutathione biosynthesis pathway. It catalyses the condensation of gamma-glutamylcysteine and glycine, to form glutathione. A defect in this enzyme results in accumulation of pyroglutamic acid and gamma-glutamylcysteine in urine and blood; decrease level of glutathione in erythrocytes; increase urinary excretion of 5-oxoproline. GSD is typically distinguished by three levels of severity. Those levels naturally being mild, moderate and severe. Being with the former, mild GSD can lead to a harmful condition known as hemolytic anemia. This occurs when red blood cells are destroyed. Although not as common, it is also possible for patients affected with GSD to excrete in their urine elevated quantities of 5-oxoproline (hence the other name for this condition shown in the first sentence of this description). The accumulation of high levels of 5-oxoproline (and hence the elevated level of secretion of this compound) is a direct consequence of glutathione being improperly processed by the body. Turning now to the second level of severity, moderate, it is typical to see affected patients experience experience the two symptoms described above, in addition to metabolic acidosis. The latter condition being the consequence of high acidity levels in the blood as well as other tissues. Finally, individuals with severe GSD may suffer from a wide variety of neurological symptoms. This could include anything from ataxia and slowed reactions, to psychomotor retardation, mental retardation and seizures.

Glycerol Kinase Deficiency (Hyperglycerolemia; Glyceroluria; GK Deficiency; GKD) is a rare metabolic disease caused by a deficiency in the GK gene which codes for glycerol kinase. A deficiency in this enzyme results in accumulation of glycerol in urine and serum. Symptoms include cryptorchism, trabismus, myopathy, lethargy, and vomiting. Treatment includes corticosteroids and acute glucose infusion.

Glycine N-methyltransferase deficiency, also called GNMT deficiency, is an autosomal recessive disorder of methionine metabolism caused by a defective glycine N-methyltransferase (GNMT). GNMT catalyzes the conversion of glycine into N-methylglycine (sarcosine) using S-adenosylmethionine (SAM or AdoMet). This disorder is characterized by a large accumulation of methionine in the plasma and transaminases in the serum. Symptoms of the disorder include hepatomegaly.

Glycogen storage disease type 1A (GSD1A), or von Gierke disease, is caused by a defect in the G6PC gene which codes for Glucose-6-phosphatase. Glucose-6-phosphatase hydrolyzes glucose-6-phosphate to glucose and is responsible for the regulation of blood glucose level. A defect in this enzyme results in accumulation of glycogen in affected tissues, like liver and kidney; decreased glucose level; and accumulation of lactate. Glycogen storage disease type 1A causes clinically significant end-organ disease with significant morbidity. Usually it presents in childhood. Symptoms include seizures, irritability, pallor, hypotonia, tremors, loss of consciousness, apnea and hepatomegaly. There is no cure for glycogen storage disease type 1A. Diet therapy can help to prevent hypoglycemia and reduce the symptoms. Liver transplantation may be indicated in cases of hepatic malignancy.